Role of the heme-related mitochondrial antioxidant ABCB10 in alcoholic liver disease

血红素相关线粒体抗氧化剂 ABCB10 在酒精性肝病中的作用

基本信息

批准号：
10443585
负责人：
Orian S Shirihai
金额：
$ 35.1万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10443585
关键词：
ATP Hydrolysis ATP phosphohydrolase ATP-Binding Cassette Transporters Alcoholic Hepatitis Alcoholic Liver Diseases Antioxidants Bilirubin Biliverdin reductase Biliverdine Cessation of life Cirrhosis Clinical Trials Cysteine Cytosol Data Defect Dependence Disease Progression Effectiveness Engineering Equilibrium Ethanol Glutathione Heme Hepatic Hepatitis Hepatocyte Human Hydrogen Peroxide Impairment Inner mitochondrial membrane Knockout Mice Liver Liver Mitochondria Measures Mediating Membrane Mitochondria Mitochondrial Matrix Molecular Mus Natural regeneration Organelles Oxidation-Reduction Oxidative Stress Patients Post-Translational Regulation Process Production Proteins Public Health Reactive Oxygen Species Role Severity of illness Sulfinic Acids Sulfonic Acids System Testing Time Virulence Factors fluorescence imaging gain of function heme oxygenase-1 hydrophilicity in vivo live cell imaging liver biopsy liver function mitochondrial dysfunction mouse model mutant overexpression oxidation oxidative damage prevent stem success

项目摘要

Project Summary Alcoholic liver disease (ALD) causes 48% of cirrhotic deaths derived from hepatitis. Increased reactive oxygen species (ROS) production is a major pathogenic factor leading the progression of ALD from steatosis to alcoholic hepatitis (AH). However, clinical trials testing compounds that unselectively scavenge ROS or enhance acquainted antioxidants were unsuccessful. This lack of success supports that ALD disrupts endogenous antioxidant systems inside mitochondria, an organelle formed by two membranes that limit the entry and action of the compounds tested. Our proposal stems from our identification of a mitochondrial antioxidant and redox system impaired in ALD and previously unknown in liver. This system is constituted by the mitochondrial inner membrane ATP binding cassette transporter ABCB10, which exports a previously unknown cargo through its ATP hydrolysis activity (ATPase). Our preliminary data supports that ABCB10 decreases ALD severity by decreasing ROS-mediated damage, as liver-specific deletion of ABCB10 exacerbates hepatic oxidative damage and ALD severity in mice. We hypothesize that ABCB10 transport activity protects from ALD by limiting EtOH-induced oxidative damage. Remarkably, our new data shows that ABCB10 content is decreased in late- stage ALD, including mice and humans with AH. Mechanistically, we show for the first time that ABCB10 exports Biliverdin (BV) from the mitochondrial matrix to the cytosol, where biliverdin reductase (BLVR) is located. Exported BV is used by cytosolic BLVR to regenerate intracellular Bilirubin (BR) destined for ROS scavenging. We hypothesize that ABCB10-mediated BV export is decreased in ALD, shrinking the intrahepatocyte BR pool that protects from ROS-mediated damage. Accordingly, our data show that: i) EtOH and ABCB10 deletion reduce intrahepatocyte BR levels and ii) ABCB10 deletion causes mitochondrial BV accumulation and increases intracellular ROS levels. Thus, we will: 1) Determine the role of ABCB10 in ALD in vivo and 2) Determine the mechanism by which ABCB10 modulates oxidative stress in ALD.

项目概要酒精性肝病 (ALD) 导致 48% 的肝炎肝硬化死亡。活性氧增加 ROS 的产生是导致 ALD 从脂肪变性进展为酒精性的主要致病因素肝炎（AH）。然而，临床试验测试了非选择性清除 ROS 或增强活性的化合物熟悉的抗氧化剂都没有成功。缺乏成功表明 ALD 会破坏内源性线粒体内的抗氧化系统，线粒体是一种由两层膜形成的细胞器，限制其进入和作用测试的化合物。我们的提议源于我们对线粒体抗氧化剂和氧化还原的鉴定酒精性肝病（ALD）中的系统受损，以前在肝脏中未知。该系统由线粒体内膜 ATP 结合盒转运蛋白 ABCB10，通过其输出以前未知的货物 ATP 水解活性（ATP 酶）。我们的初步数据支持 ABCB10 将 ALD 严重程度降低减少 ROS 介导的损伤，因为肝脏特异性删除 ABCB10 会加剧肝脏氧化损伤和小鼠 ALD 严重程度。我们假设 ABCB10 转运活性通过限制 ALD 来预防 ALD 乙醇引起的氧化损伤。值得注意的是，我们的新数据显示 ABCB10 含量在后期有所下降- 阶段 ALD，包括患有 AH 的小鼠和人类。从机制上讲，我们首次展示了 ABCB10 输出胆绿素 (BV) 从线粒体基质转移到细胞质，胆绿素还原酶 (BLVR) 就位于细胞质中。细胞质 BLVR 使用输出的 BV 来再生用于清除 ROS 的细胞内胆红素 (BR)。我们假设 ALD 中 ABCB10 介导的 BV 输出减少，从而导致肝细胞缩小 BR 池可防止 ROS 介导的损伤。因此，我们的数据表明： i) EtOH 和 ABCB10 缺失降低肝细胞内 BR 水平，ii) ABCB10 缺失导致线粒体 BV 积累，增加细胞内活性氧水平。因此，我们将：1) 确定 ABCB10 在体内 ALD 中的作用，2) 确定 ABCB10 调节 ALD 氧化应激的机制。